The compound rilapladib is described and exemplified, for example, in PCT publication WO02/30904A1, published Apr. 18, 2002 and its worldwide counterparts, the subject matter of which is incorporated herein by reference in their entirety. The compounds disclosed in this application, including rilapladib, are inhibitors of the enzyme Lp-PLA2 and as such are expected to be of use in therapy in disorders mediated by Lp-PLA2 activity such as the disorders disclosed therein. For example, such diseases may be associated with increased involvement of monocytes, macrophages or lymphocytes, with the formation of lysophosphatidylcholine and oxidised free fatty acids, with lipid oxidation in conjunction with Lp-PLA2 activity, or with endothelial dysfunction. Examples of such diseases include atherosclerosis, diabetes, hypertension, angina pectoris, rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, ischaemia, reperfusion injury, sepsis, acute inflammation, chronic inflammation, and psoriasis. Other disorders associated with Lp-PLA2 activity have been described in the art. Rilapladib is currently in a Phase 2 clinical study relating to treatment of Alzheimer's Disease. See, e.g., ClinicalTrials.gov, Study NCT01428453.
Prior to the present invention, two forms of rilapladib had been recognized. A crystalline form of rilapladib had been identified and for the sake of identification had been termed “Form 1”. Another form, termed “Form 2” for the sake of identification, was less well defined. Without intending to be bound, Form 2 is thought to be a channel entity which is able to incorporate a range of solvents. While broadly similar and clearly related, solid state characterizations such as XRPD and others may vary for products termed “Form 2” depending on the solvent composition.
WO02/30904A1 Example 5 relating to a preparation of rilapladib does not describe the resulting crystalline form and in particular does not describe the new crystal form according to the present invention. The sample prepared in accordance with Example 5 has been found by XRPD and Raman spectroscopy to comprise Form 1 and Form 2 rilapladib, with no evidence within detection limits of the novel form according to the present invention.
In the course of several experiments, it has now been unexpectedly discovered that rilapladib can be prepared as a new and advantageous crystalline form which for the sake of identification is termed herein as “Form 3”.